Field of the Invention
The disclosure refers to compounds that, in addition to enhancing the sensitivity to acetylcholine and choline, and to their agonists, of neuronal cholinergic receptors, and/or acting as cholinesterase inhibitors and/or neuroprotective agents, have enhanced blood-brain barrier permeability in comparison to their parent compounds. The compounds are derived (either formally by their chemical structure or directly by chemical synthesis) from natural compounds belonging to the class of amaryllidaceae alkaloids e.g., Galantamine, Narwedine and Lycoramine, or from metabolites of said compounds. The compounds of the present invention can either interact as such with their target molecules, or they can act as “pro-drugs”, in the sense that after reaching their target regions in the body, they are converted by hydrolysis or enzymatic attack to the original parent compound and react as such with their target molecules, or both. The compounds of this disclosure may be used as medicaments for the treatment of human brain diseases associated with a cholinergic deficit, including the neurodegenerative diseases Alzheimer's and Parkinson's disease and the neurological/psychiatric diseases vascular dementia, schizophrenia and epilepsy. Galantamine derivatives disclosed herein have higher efficacy and lower levels of adverse side effects in comparison to galantamine, in treatment of human brain diseases.
Description of the Related Art
The diffusion of compounds from the blood plasma into the brain is complicated by the presence of the blood-brain barrier that is a membrane that segregates the brain interstitial fluid from the circulating blood. In designing drugs active in the central nervous system and able to cross the blood-brain barrier, one can exploit endogenous active mechanisms, utilize proper delivery techniques or modify the chemical structure through the synthesis of pro-drug derivatives.
Galantamine is an alkaloid that can be isolated from the bulbs of various snowdrop (Galanthus) and narcissus species (daffodils, Amaryllidaceae), and recently in particularly high concentrations from Lycoris radiata, and related species. Synthetic Galantamine hydrobromide is manufactured by, among other companies, Sanochemia and Janssen Pharmaceutica. The drug has been approved in more than 70 nations for the treatment of mild-to-moderate Alzheimer's disease (AD), a neurodegenerative brain disease. Extensive studies of the pharmacokinetic profile, tissue distribution and accumulation of Galantamine in mice, rats, rabbits and dogs have shown that Galantamine given orally is by no means preferentially distributed to the brain where it is supposed to exert its therapeutic activity in said brain diseases. In contrast, it is accumulated at much higher concentrations in other body tissues. In male and female rat tissues the highest concentrations are observed in kidney (tissue to plasma ratio; T/P˜10-15), salivary and adrenal gland (T/P˜7-14), female rat spleen (T/P˜20), lung, liver, heart, skeletal muscle and testes (T/P˜2-4). In contrast, the brain to plasma ratio is only T/P˜1.5. Similarly, the brain/plasma partition coefficient Kbrain is significantly lower than most other Korgan of Galantamine.
Limited penetration ability of Galantamine through the blood-brain barrier (BBB) into the central nervous system (CNS) is indicated also by the compound's log P value of 1.3, log P being defined as the decadic logarithm of the partition coefficient P which is the ratio of the concentration of compound in aqueous phase to the concentration of compound in immiscible solvent, as the neutral molecule. The log P value is obtained by predictive computational methods and provides a general guideline as to whether a drug gains rapid access to the CNS, or not. Thus, it has been established over the past more than 30 years that, assuming passive absorption, drugs with optimum CNS penetration generally have log P values around or somewhat above 2. Significantly lower log P values are often associated with low brain-to-plasma and high non-brain tissue-to-plasma ratios (see above: log P and T/P ratios for Galantamine). However, much higher log P values are also of disadvantage, as high lipophilicity is often associated with toxicity, non-specific binding, insufficient oral absorption and limited bioavailability. It follows from this account that BBB penetration and T/P ratios are essential parameters to be considered in the case of drugs that are supposed to act mainly or exclusively in the central nervous system.
Other important parameters controlling BBB penetration of a compound are the total polar surface area, the existence of ionizable groups on the molecule and the affinity of binding to biological membranes as compared to the affinity of binding to serum albumin. The latter data set is often used to scrutinize calculated log P values. In those cases in which special transport systems do not play a major role for the transport of a compound through the BBB, the predictions of lipophilicity and BBB penetration properties are quite suitable for the design of derivatives that transfer the BBB more efficiently than the parent compound.
The present disclosure relates to methods by which the lipophilicity and/or BBB penetration and/or brain-to-plasma ratio of a compound is enhanced by formation of a reversible linkage with one or more suitable groups so as to yield “pro-drugs”, i.e., chemical derivatives that, after having passed through the blood-brain barrier, are converted (back) to the original compound itself inside the patients brain. Liberation of the parent compound may be by chemical hydrolysis or enzymatic attack, or by redox reactions. In another embodiment, the present invention refers to compounds that after chemical modification of the base compound have achieved a lopP value more favourable for BBB penetration, with these derivatives acting as such at their target molecules in the patient's brain.
The plant alkaloid galantamine has been described as a cholinesterase inhibitor (ChE-I) and as a nicotinic acetylcholine receptor (nAChR) sensitizing agent (APL; allosterically potentiating ligand), and galantamine has been proposed for the treatment of several human brain diseases, including Alzheimer's disease (AD). Presently, the compliance of Alzheimer patients to treatment with ChE-I and APL is rather low, of the order of 20%, a key reason being the adverse effects nausea, diarrhea, vomiting, anorexia and muscle cramps. In the case of galantamine, the majority of these adverse effects is due to actions of the drug while passing through the gastro-intestinal tract, and to its rather limited permeation through the blood-brain barrier (BBB) into the brain. To help patients coping with the adverse effects of galantamine, the manufacturer's recommended daily dose of the drug is limited to 16-24 mg per day, and this dose is slowly reached by stepwise dose increase, beginning at 4 mg/day and over a period of 2-3 months.
The rather low levels of accumulation of galantamine in the brain, when administered as the unmodified drug, are a serious disadvantage with respect to the drug's therapeutic use, i.e., for the treatment of cognitive disorders, such as AD. As indicated by the brain-to-plasma ratio of ˜1.3, only a small part of the administered drug reaches the brain, and the high levels of the drug in other (peripheral) tissues cause most, if not all, of the observed adverse effects. The mostly peripheral action of galantamine is also indicated in its previous use for the treatment of a number of neuromuscular disorders, including Myasthenia gravis and poliomyelitis.
In WO2007/039138 reference is made to the low hydrophobicity and related limited partition into the human brain of galantamine, and several procedures for overcoming these drawbacks of a medication that is supposed to act on target molecules located in the brain's central nervous system are proposed. In the same document numerous derivatives of galantamine that significantly improve transport of the respective compound through the blood-brain barrier (BBB) are described and they are proposed as drugs for the treatment of a variety of diseases associated with cognitive deficits.
Presently approved drugs for the treatment of Alzheimer's disease (AD) have in common that they all target excitatory neurotransmission in the brain, namely the cholinergic and the glutamatergic systems. Three of the four presently available drugs (Donepezil, Rivastigmin, Galantamine, Memantine) are cholinergic enhancers (Donepezil, Rivastigmin, Galantamine) in that they all inhibit the family of acetylcholine-degrading enzymes denoted as cholinesterases (ChE). Inhibition of ChE increases the synaptic concentrations of acetylcholine (ACh), thereby enhancing and prolonging the action of ACh on muscarinic (mAChR) and nicotinic (nAChR) acetylcholine receptors. In addition to acting as ChE inhibitor, Galantamine also acts by allosterically stimulating (sensitizing) cholinergic receptors. Allosteric sensitization of nicotinic receptors enhances their activation by ACh or choline (Ch), thereby correcting for a disease-associated deficit in transmitter or receptor concentration (Maelicke A & Albuquerque E X (1996) Drug Discovery Today 1, 53-59; Maelicke A & Albuquerque E X (2000) Eur J Pharmacol 393, 165-170). In addition to their therapeutic benefits, these drugs induce adverse peripheral and central side effects; the muscarinic ones including nausea, vomiting and diarrhea, and the nicotinic ones including tremors and muscle cramps. From meta data (Cochrane reviews, (2004), Issue 4) and direct comparison clinical studies (Wilcock G K et al. (2000) Brit Med Journ 321:1-7), the relatively weakest of the three presently used ChE inhibitors, Galantamine, has the highest clinical efficacy, with the therapeutic benefit achieved at concentrations that are well below those required for effective inhibition of AChE (Raskind M A et al. (2000) Neurology 54, 2261-2268; Maelicke A & Albuquerque E X (2000) Eur J Pharmacol 393, 165-170). It has been suggested that the higher therapeutic efficacy of Galantamine, as compared to the other two available ChE inhibitors, is due to an additional or alternative mode of action, i.e., allosteric sensitization of nAChR (Maelicke A & Albuquerque E X (1996) Drug Discovery Today 1, 53-59).
Galantamine enhances nicotinic cholinergic neurotransmission by acting directly on nicotinic receptors (Schrattenholz A et al. (1996) Mol Pharmacol 49, 1-6; Samochocki M et al. (2003) J Pharmacol Exp Therap 305, 1024-1036). The drug binds to a distinct allosteric site on these receptors (Schröder B et al. (1993) J Biol Chem 269, 10407-10416), from which it acts synergistically with acetylcholine (or choline) to facilitate nAChR activation (Maelicke A & Albuquerque E X (1996) Drug Discovery Today 1, 53-59; Maelicke A & Albuquerque E X (2000) Eur J Pharmacol 393, 165-170). Compounds acting like Galantamine in this way are referred to as “allostericaly potentiating ligands (APL)” (Schrattenholz A et al. (1996) Mol Pharmacol 49, 1-6, Maelicke A & Albuquerque E X (2000) Eur J Pharmacol 393, 165-170).
The APL action on human nicotinic receptors has been demonstrated by electrophysiological studies using human brain slices (Alkondon, M. et al., (2000) J Neurosci 20, 66-75) and human recombinant cell lines each expressing a single nAChR subtype (Samochocki M et al (2000) Acta Neuro Scand Suppl 176, 68-73, Samochocki M et al. (2003) J Pharmacol Exp Therap 305, 1024-1036). All human nAChR subtypes analysed so far are sensitive to enhancement by APL. In the presence of Galantamine, the binding affinity and channel opening probability of nAChR are increased, leading to a decrease in EC50 for ACh between 30% and 65% (Samochocki M et al (2000) Acta Neuro Scand Suppl 176, 68-73, Samochocki M et al. (2003) J Pharmacol Exp Therap 305, 1024-1036). Furthermore, Galantamine increases the slope of the dose-response curve for ACh, which has been interpreted as an increase in the cooperativity between nAChR subunits (Maelicke A & Albuquerque E X (1996) Drug Discovery Today 1, 53-59).
The APL effect of Galantamine is observed at submicromolar concentrations (Samochocki M et al (2000) Acta Neuro Scand Suppl 176, 68-73, Samochocki M et al. (2003) J Pharmacol Exp Therap 305, 1024-1036), i.e., below the concentration range at which ChE inhibition takes place. The two modes of action of nicotinic APL are independent of each other, as was shown by ion flux studies (Okonjo K et al (1991) Eur J Biochem 200, 671-677; Kuhlmann J et al (1991) FEBS Lett 279, 216-218) and electrophysiological studies of brain slices from both rats and humans (Santos M D et al (2002) Mol Pharmacol 61, 1222-1234). In these studies, when cholinesterase activity was completely blocked by either reversible or irreversible blocking agents, the nicotinic APL, e.g., Galantamine, still was able to produce an APL effect of the same size as in the absence of the other ChE inhibitors. Of the cholinesterase inhibitors presently approved as AD drugs, Galantamine is the only one with nicotinic APL activity (Maelicke A et al (2000) Behav Brain Res 113, 199-206).
The use of Galantamine and other APL as a drug treatment strategy for cognitive disorders, including AD and PD was proposed in 1996 (Maelicke A & Albuquerque E X (1996) Drug Discovery Today 1, 53-59). Later, the proposal was extended to vascular and mixed dementia (Maelicke A et al (2001) Biol Psychiatry 49, 279-288), schizophrenia, epilepsy and other diseases with a nicotinic cholinergic deficit.
The comparatively low levels of accumulation of Galantamine in the brain are a serious disadvantage with respect to the drug's therapeutic use, i.e., for the treatment of cognitive disorders, such as AD. As indicated by the T/P ratios, only a small part of the administered drug reaches the brain, and the high levels of the drug in other (peripheral) tissues may be responsible for some of the observed adverse side effects. As a point in case, long before having been approved for the treatment of AD, Galantamine has primarily been used for the treatment of a number of neuromuscular disorders, including Myasthenia gravis and poliomyelitis.
EP-A 648 771, EP-A 649 846 and EP-A 653 427 all describe Galantamine derivatives, a process for their preparation and their use as medicaments, however none of these applications considers ways and means of enhancing penetration through the blood-brain barrier and brain-to-plasma ratio of base compounds and derivatives.
U.S. Pat. No. 6,150,354 refers to several Galantamine analogues for the treatment of Alzheimer's disease. However, selective chemical modification for the purpose of increasing penetration through the blood-brain barrier is not considered.
WO 01/74820, WO 00/32199 and WO 2005030333 refer to derivatives and analogues of Galantamine for the treatment of a variety of human brain and other diseases, and acute functional brain damage. However, selective chemical modifications or other means of improving blood-brain barrier penetration are not considered.
WO 88/08708, WO 99/21561, WO 01/43697 and US 2003/0162770 refer to derivatives and analogues of Galantamine for the treatment of various cognitive symptoms. However, selective chemical modifications or other means of improving blood-brain barrier penetration are not considered.
WO 2005/030713 refers to a method for the synthesis of optical isomers of Galantamine from a Narwedine bromoamide derivative. However, it does not deal with other derivatives of Galantamine, or their use as medicaments, or chemical modifications aimed at enhancing blood-barrier penetration of said compounds.
WO 97/40049 describes several derivatives of benzazepines and related compounds that may be applied for the treatment of Alzheimer's disease. However, no concept is provided in this application for increasing the penetration of compounds through the blood-brain barrier.